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| Gene | HRAS |
| Variant | G12K |
| Impact List | missense |
| Protein Effect | loss of function - predicted |
| Gene Variant Descriptions | HRAS G12K does not lie within any known functional domains of the Hras protein (UniProt.org). G12K is transforming in cultured cells (PMID: 6092966), and can be predicted to lead to a loss of Hras protein function and activation of downstream signaling based on the effects of other HRAS G12 mutations. |
| Associated Drug Resistance | |
| Category Variants Paths |
HRAS mutant HRAS act mut HRAS G12K HRAS mutant HRAS G12X HRAS G12K |
| Transcript | NM_005343.4 |
| gDNA | chr11:g.534287_534289delGGCinsAAG |
| cDNA | c.34_36delGGCinsAAG |
| Protein | p.G12K |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_176795.4 | chr11:g.534287_534289delGGCinsAAG | c.34_36delGGCinsAAG | p.G12K | RefSeq | GRCh38/hg38 |
| NM_176795 | chr11:g.534287_534289delGCCinsCTT | c.34_36delGGCinsAAG | p.G12K | RefSeq | GRCh38/hg38 |
| NM_005343 | chr11:g.534287_534289delGCCinsCTT | c.34_36delGGCinsAAG | p.G12K | RefSeq | GRCh38/hg38 |
| NM_176795.5 | chr11:g.534287_534289delGGCinsAAG | c.34_36delGGCinsAAG | p.G12K | RefSeq | GRCh38/hg38 |
| NM_005343.4 | chr11:g.534287_534289delGGCinsAAG | c.34_36delGGCinsAAG | p.G12K | RefSeq | GRCh38/hg38 |
| NM_001130442 | chr11:g.534287_534289delGCCinsCTT | c.34_36delGGCinsAAG | p.G12K | RefSeq | GRCh38/hg38 |
| NM_005343.3 | chr11:g.534287_534289delGGCinsAAG | c.34_36delGGCinsAAG | p.G12K | RefSeq | GRCh38/hg38 |
| NM_001130442.2 | chr11:g.534287_534289delGGCinsAAG | c.34_36delGGCinsAAG | p.G12K | RefSeq | GRCh38/hg38 |
| NM_001130442.3 | chr11:g.534287_534289delGGCinsAAG | c.34_36delGGCinsAAG | p.G12K | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| HRAS mutant | transitional cell carcinoma | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS missense (Q61R, G12S, G13R) or frameshift (V29Cfs*19) mutations, progression-free survival was significantly improved in patients harboring HRAS mutations (5.1 vs 0.8 months, HR=0.262) compared to wild-type patients (PMID: 32636318; NCT02535650). | 32636318 |
| HRAS mutant | breast cancer | decreased response | PI-273 | Preclinical - Cell culture | Actionable | In a preclinical study, breast cancer cell lines harboring RAS mutations, including HRAS-mutant cell lines, demonstrated decreased sensitivity to growth inhibition by PI-273, in culture (PMID: 28827373). | 28827373 |
| HRAS mutant | salivary gland cancer | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial (KO-TIP-001), Zarnestra (tipifarnib) treatment resulted in an objective response rate of 8% (1/12) in patients with recurrent or metastatic salivary gland cancer harboring HRAS mutations, with a median progression-free survival of 7 months (J Clin Oncol 38: 2020 (suppl; abstr 6504); NCT02383927). | detail... |
| HRAS mutant | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, head and neck squamous cell carcinoma cell lines harboring an HRAS mutation were sensitive to treatment with Zarnestra (tipifarnib), demonstrating reduced cell growth and decreased phosphorylation of Erk and Mek, and inhibition of spheroid viability in culture (PMID: 32727882). | 32727882 |
| HRAS mutant | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial (AIM-HN), Zarnestra (tipifarnib) demonstrated safety and preliminary activity in patients with recurrent or metastatic head and neck squamous cell carcinoma harboring mutations in HRAS, resulting in an objective response rate of 20% (10/50, 1 complete and 9 partial responses), disease control rate of 48% (24/50), with stable disease in 14 patients, median progression-free survival of 2.6 mo, and median overall survival of 7 mo (Ann Oncol (2023) 34 (suppl_2): S1286-S1287; NCT03719690). | detail... |
| HRAS mutant | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial (KO-TIP-001), Zarnestra (tipifarnib) treatment resulted in an objective response rate of 55% (11/20) in patients with head and neck squamous cell carcinoma harboring HRAS missense mutations at a variant allele frequency over 20%, with nine patients achieved stable disease and a median progression-free survival of 5.6 months (PMID: 33750196; NCT02383927). | 33750196 |
| HRAS mutant | medullary thyroid carcinoma | sensitive | Cabozantinib | Guideline | Actionable | Cometriq (cabozantinib) is included in guidelines for patients with advanced or metastatic medullary thyroid carcinoma harboring RAS mutations (PMID: 31549998, PMID: 35491008; ESMO.org). | 35491008 31549998 detail... |
| HRAS mutant | medullary thyroid carcinoma | sensitive | Cabozantinib | Phase III | Actionable | In a Phase III trial, Cometriq (cabozantinib) treatment resulted in improved progression-free survival (47 vs 8 weeks, HR 0.15, p=0.0317) compared to placebo in thyroid medullary carcinoma patients harboring RAS mutations (PMID: 27525386). | 27525386 |
| HRAS mutant | ovarian cancer | predicted - sensitive | Alpelisib + Binimetinib | Phase Ib/II | Actionable | In a Phase Ib study, Alpelisib (BYL719) in combination with Binimetinib (MEK162) demonstrated preliminary safety and efficacy in patients with RAS-mutant advanced solid tumors, including patients with ovarian cancer (J Clin Oncol 32:5s, 2014 (suppl; abstr 9051). | detail... |
| HRAS mutant | urinary bladder cancer | sensitive | Metformin | Preclinical | Actionable | In a preclinical study, mouse models of bladder cancer harboring an HRAS mutation were sensitive to Glucophage (metformin), resulting in tumor growth reduction and prevention of hyperplasia regression (PMID: 26921394). | 26921394 |
| HRAS mutant | Advanced Solid Tumor | predicted - sensitive | Binimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, Binimetinib (MEK162) inhibited growth and induced apoptosis in human solid tumor cell lines harboring HRAS mutations in culture (PMID: 26544513). | 26544513 |
| HRAS mutant | transitional cell carcinoma | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, human urinary transitional cell carcinoma cells harboring mutant HRAS were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
| HRAS mutant | endometrial cancer | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human endometrial cancer cells harboring mutant HRAS in culture (PMID: 26343583). | 26343583 |
| HRAS mutant | Advanced Solid Tumor | predicted - sensitive | Everolimus | Preclinical - Cell culture | Actionable | In a preclinical study, human solid tumor cell lines harboring HRAS mutations demonstrated increased sensitivity to growth inhibition by Afinitor (everolimus) in culture compared to cell lines with wild-type HRAS (PMID: 26544513). | 26544513 |
| HRAS mutant | Advanced Solid Tumor | predicted - sensitive | Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, human solid tumor cell lines harboring HRAS mutations demonstrated increased sensitivity to growth inhibition by Selumetinib (AZD6244) in culture compared to cell lines with wild-type HRAS (PMID: 26544513). | 26544513 |
| HRAS act mut | transitional cell carcinoma | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated safety and preliminary efficacy in patients with metastatic urothelial carcinoma harboring HRAS mutations (n=14) or STK11:rs2075606, 3 of 4 patients achieved progression-free survival at 6 months harbored HRAS activating mutations, and no response was observed in HRAS wild-type patients (J Clin Oncol 38: 2020 (suppl; abstr 5086); NCT02535650). | detail... |
| HRAS act mut | salivary gland carcinoma | sensitive | Tipifarnib | Clinical Study | Actionable | In a clinical study, Zarnestra (tipifarnib) treatment resulted in an overall response rate of 8% (n=13) with one ongoing partial response with a duration of 14 months and stable disease as the best response in 58% (7/12) of evaluable patients with HRAS-mutant metastatic salivary gland carcinoma, and a median overall survival of 18 months, and a median progression-free survival of 7 months (PMID: 32557577). | 32557577 |
| HRAS act mut | Advanced Solid Tumor | no benefit | Selumetinib | Clinical Study - Cohort | Actionable | In a Phase II trial (Pediatric MATCH), Koselugo (selumetinib) treatment was tolerated but did not result in an objective response in pediatric patients with advanced solid tumors including high-grade glioma (n=8) and rhabdomyosarcoma (n=7) harboring MAPK pathway alterations including BRAF V600E (n=2), activating KRAS (n=8)/HRAS (n=1)/NRAS (n=3) or inactivating NF1 (n=7) mutations, with a 6-month progression-free survival of 15% (3/20) and 3 stable disease as best response (PMID: 35363510; NCT03213691). | 35363510 |
| HRAS act mut | Advanced Solid Tumor | predicted - sensitive | BAY 11-7082 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, BAY 11-7082 induced apoptosis and decreased Akt signaling, viability, and colony formation in cancer cells harboring activating HRAS mutations in culture and inhibited tumor growth in a cell line xenograft model (PMID: 38982514). | 38982514 |